Chronic kidney disease (CKD) has both a clinical description (reduced kidney function and protein in the urine) and a pathological description (nephrosclerosis as characterized by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis). Both occur with age, but little is known about their relationship to each other. The goal of this study is to characterize age-related changes in the kidney in a large sample of living kidney donors at two sites (Mayo Clinic and Cleveland Clinic), to identify biomarkers that predict these changes, and to eventually relate renal pathology and biomarkers that detect renal pathology to clinical outcomes in future studies. Combining computed tomography (CT) scan findings (total renal cortex volume) and renal biopsy findings (glomeruli per renal cortex unit volume) allows estimation of nephron endowment (total number of nephrons a person is born with). Our central hypothesis is that with aging, progressive nephrosclerosis leads to atrophy of nephrons with cortical volume loss and scarring. This volume loss is initially compensated by hypertrophy of viable nephrons, which leads to further nephrosclerosis. Eventually, however, volume loss from nephrosclerosis overwhelms the compensatory hypertrophy of remaining nephrons and the kidneys decrease in size. Aim 1. To test the hypothesis that age, GFR, urine albumin, and CKD risk factors associate with A) macro- anatomy findings of decreased renal cortical volume and focal scarring on CT scan among adults undergoing a standardized evaluation for potential kidney donation (n=4300), and B) micro-anatomy findings of nephrosclerosis and nephron size on renal biopsy among adults who actually donate a kidney (n=2500), and furthermore, to determine if increased nephron endowment is protective against age-related nephrosclerosis and the increased size of viable nephrons. Aim 2. To test the hypothesis that 10 novel serum and urine biomarkers for CKD (e.g., kidney injury molecule 1) associate with age-related changes A) in decreased renal cortical volume and focal scarring by CT scan (1500 potential donors) and B) in nephrosclerosis and nephron size by renal biopsy (1000 actual donors). PUBLIC HEALTH RELEVANCE: As adults age, some of the healthy tissue in the kidney is gradually replaced by scar tissue. We plan to determine whether clinical tests can detect these age-related changes in the kidney. This will improve our understanding of how chronic kidney disease develops in people as they age and eventually lead to better ways to diagnose, prevent, and treat chronic kidney disease.